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R. V. Rajala, A. Rajala, V. K. Gupta; Insulin Receptor Signaling Regulates Mitochondrial Integrity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1105.
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© ARVO (1962-2015); The Authors (2016-present)
Insulin receptor (IR)/phosphoinositide 3-kinase (PI3K)/Akt signaling is known to regulate mitochondrial integrity by maintaining the driving force for ATP production, which increases intracellular ATP levels and inhibits cell death. Hexokinases are known to bind voltage-dependent anion channel (VDAC) and directly couple intra-mitochondrial ATP synthesis to glucose metabolism. In the absence of Akt activation, glycogen synthase kinase-3β (GSK-3β) phosphorylates VDAC and thereby blocks the interaction of hexokinase (HK) with VDAC. Akt directly phosphorylates GSK-3β and inhibits its function. We previously reported that physiological light activates the IR signaling pathway in rods. The IR activation is functionally important for rod survival, since its deletion from rods resulted in the loss of neuroprotective survival signaling. We recently found that the cone-specific deletion of PI3K, the enzyme activated by the IR, resulted in an age-related cone degeneration. In this study we examined relationship between light-induced activation of IR and mitochondrial integrity.
Mitochondria were prepared from dark- and light- adapted wild type and conditional rod-specific IR knockout mice. Equal amount of mitochondrial proteins were subjected to immunoblot analysis with HK and VDAC antibodies. Retinal ex vivo organ cultures were incubated with GSK-3β inhibitor and examined the binding of hexokinase to VDAC.
Our data indicate that light-induced activation of IR resulted in the translocation of hexokinase to mitochondria, and this light-dependent translocation of HK is inhibited in IR-/- mouse retinas. Our studies show that addition of GSK-3β inhibitor to retinal ex vivo organ cultures resulted in the enhancement of binding of HK to mitochondria.
Our results indicate that IR activation regulates the mitochondrial integrity. Our studies also suggest that blocking the GSK-3β would enhance the mitochondrial integrity. Pharmacological agents that enhance the binding of HK to mitochondria would preserve the mitochondrial integrity and thereby protect the dyeing retinal cells in retinal degenerations.
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